III. Pathologies

As reviewed in Greggio et al, many lineage tracing systems have been used to investigate the latent differentiation potential of embryonic progenitors and adult pancreatic cells, under normal or regenerative conditions, in order to identify an elective adult stem cell reservoir.3 Under physiological conditions, α, β, ductal, and acinar cells are maintained by self-duplication of pre-existing cells, while the scenario is different in the context of pancreas regeneration after severe damage: α cells are able to transdifferentiate into β cells (as, rarely, acinar and ductal cells), thanks to the induction of neurogenin 3 (Ngn 3).

A. Regenerative conditions: cellular ablation and pancreatic ligation

In vivo cellular responses to pancreatic damage (after injury) are multiple: cell reprogramming, proliferation of remaining sister cells, transient reprogramming of cells that promote healing, and proliferation of adult stem/progenitor cells (Pedro Herrera lecture). Pedro Herrera et al developed a model
of cell-specific ablation using RIP-DTR mice, mice that express diphtheria toxin receptor on the β-cell surface, allowing β-cell ablation after injection of diphtheria toxin (wild-type mice are unresponsive to this toxin). Thorel et al showed that a pool of only 2% of α cells are able to dedifferentiate into
bihormonal cells expressing both insulin and glucagon and then differentiate into insulin+ cells, thus normalizing glycemia (Figure 2).9 Interestingly, total β-cell ablation is not required for α to β conversion, and this conversion occurs independently of the model of β-cell deletion (streptozotocin, alloxane, or DTR). In addition, the blockade of glucagon receptor may be useful to expand α-cell mass before conversion into β cells.10

neogenesis due to reprogramming of both endocrine and ductal cells (Luc Baeyens lecture). Briefly, in adult mice with pancreas severely injured by PDL, Ngn3+ cells appear near duct epithelium and differentiate into β cells. Yuchi et al demonstrated that estrogens (E2) and their receptor ERα were necessary for β-cell replication and formation in mouse pancreas.11 Acinar cells from exocrine pancreas are also able to convert into cells resembling β cells in diabetic mice; the regenerative process depends on Stat3 signaling and requires a threshold number of Ngn3+ acinar cells. Baeyens et al showed that the transient administration of EGF (epidermal growth factor) and CNTF (ciliary neurotrophic factor) efficiently stimulates the conversion of acinar cells into β-like cells.12

B. β-Cell dedifferentiation and reprogramming in a setting of type 2 diabetes (T2D)

Regarding pathophysiological constraints such as glucolipotoxicity (consequences of a high-fat, high-sucrose diet), islet inflammation leads to β-cell death, β-cell dysfunction, and β-cell dedifferentiation and reprogramming (Yuval Dor lecture). In particular, the pancreatic fetal hormones gastrin and ghrelin reappear in human T2D islets, suggesting that pancreatic β-cell dedifferentiation could be a key mechanism of diabetic β-cell failure, rather than β-cell death. The transcription factor Pax6 is mechanistically involved: it helps to differentiate the β cell; when it is deleted, all β-cell genes are repressed while ghrelin and gastrin are derepressed.13 Domenico Accili et al examined the contribution of these two processes—β-cell death vs dedifferentiation—
in diabetic failure, using mice with deleted FoxO1, a transcription factor that integrates signals regulating β-cell mass, in β cells. Mice became hyperglycemic, and lineage-tracing experiments demonstrated that loss of β-cell mass was due to β-cell dedifferentiation, not death. Dedifferentiated β cells reverted to progenitor-like cells expressing Ngn3, Oct4, Nanog, and L-Myc. A subset of FoxO1-deficient β cells adopted the α-cell fate, resulting in hyperglucagonemia (Domenico Accili lecture) (Figure 3). As the same sequence of events is identified in different models of T2D, the authors suggested that
treatment of β-cell dysfunction should preferentially restore differentiation rather that β-cell replication.14

The Roland Stein lecture strengthened the roles of Pdx1 coregulators. Pdx1 being a master regulator of pancreas development, total Pdx1 knockout is lethal due to pancreas agenesis while a conditional knockout in adult β cell leads to hyperglycemia, glucose intolerance, β-cell loss, and α-cell increase, logically pointing to β-cell dedifferentiation. McKenna et al focused on the influence of the Swi/Snf chromatin remodeller on Pdx1 action, as chromatin remodelling activities are crucial for developmental lineage determinations and adult β-cell function. They showed that the dynamic recruitment of functionally distinct Swi/Snf chromatin re-modelling complexes, namely Brg1 and Brm, modulates Pdx1 activity in islet β cells.15